AUGUST 2, 2011, 3:46PM
By Aleea Farrakh Khan
Ovarian cancer has proven to be a very difficult cancer to diagnose at a curable stage and thus treat successfully. Even though it has one of the highest mortality rates of all gynecological cancers in the United States, there are no validated or proven screening tests, making it a challenge to diagnose at an early stage. To date, there is no evidence that any of the various screening tests that are performed, including pelvic examinations, transvaginal ultrasounds and a CA-125 assay (a test that measures the level of CA-125 in the blood to see if it is elevated), leads to a decrease in ovarian cancer deaths. These tests have not been shown to diagnose ovarian cancer early, and the risk of falsely calling a benign mass a cancer when it is not present is unacceptably high. This can lead to unnecessary surgery, treatments, and stress for patients.
Ovarian cancer symptoms are fairly non-specific, therefore only about 19 percent of all cases are detected at an early, localized stage. In the U.S. alone, an estimated 22,000 women will be diagnosed with, and 15,000 women will die from this disease in 2011. Even with all these challenges, researchers have made important clinical advances over the years in chemotherapy regimens, surgery techniques and biologic therapies to find better treatment options for ovarian cancer patients.
Three-panel drawing of stage IA, IB, and IC ovarian cancer. Credit: Terese Winslow
The image above depicts stage IA, IB, and IC ovarian cancer. The first panel shows a stage IA tumor inside one ovary. The second panel shows two stage IB tumors, one inside each ovary. The third panel shows two stage IC tumors, one inside each ovary, and one tumor has a ruptured capsule. An inset shows cancer cells floating in the peritoneal fluid surrounding abdominal organs.
The primary surgical objective in ovarian cancer treatment is removal of the tumor. It has been shown consistently that the more complete the resection, or removal of the tumor, the better the clinical outcome since the current surgical aim is removal of disease to the point that there is no visible disease present. However, not every woman can undergo such surgery. This fact led to a trial, recently reported by the European Organization for Research and Treatment of Cancer–Gynecologic Cancer Group (EORTC–GCG) and the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) examining the question of whether surgery should precede chemotherapy or if chemotherapy should come first, a method called neoadjuvant chemotherapy. Results demonstrated that there was no difference between the approaches and that neoadjuvant chemotherapy could be considered, given the similar survival outcomes and the increased side-effects of primary surgery. Newer GOG trials will allow physicians and their patients to elect neoadjuvant therapy or traditional chemotherapy after primary surgical debulking, or removal of the malignancies.
Cisplatin crystals, a platinum compound used as a chemotherapy drug.
In 1978, the U.S. FDA approved cisplatin, a chemotherapy drug containing platinum, for treatment of metastatic ovarian cancer. Shortly after that approval, the delivery of anticancer drugs intraperitoneally (IP) was established—a technique where chemotherapy drugs are administered through a surgically implanted catheter, allowing passage of fluids into the abdominal cavity. This method allows direct administration of drugs to the intra-abdominal cancer, creating higher local drug exposure. Some of the drugs used intraperitoneally, such as cisplatin and its close relative carboplatin, are also absorbed into the general circulation and assist with attacking ovarian cancer that has spread to other parts of the body.
The next significant pharmaceutical advancement was the approval of paclitaxel in the mid-90’s; the first of a class of drugs known as taxanes. Paclitaxel interferes with cell growth and division in rapidly dividing cells, such as cancer cells. Unlike the platinums, the taxanes do not get absorbed when administered into the abdominal cavity and thus provide high local drug exposure.
Researchers studied both cisplatin and paclitaxel extensively and found that chemotherapy regimens that contain both types of drugs are most effective in preventing recurrence of ovarian cancer and improving a woman’s survival period. The combination of cisplatin and paclitaxel has become the standard recommended therapy for treatment for women with ovarian cancer who may benefit from chemotherapy. Further improving this method in 2006, a study by the Gynecologic Oncology Group (GOG) showed that women with advanced ovarian cancer who receive a combination of intravenous (IV) and IP chemotherapy post-surgery extended their overall survival by about a year. The combined method of delivering drugs into the vein and directly into the abdomen simultaneously allows for improved progression-free survival. It is possible that this was due to the intra-abdominal administration of the drugs; however, more total chemotherapy was administered on the combination IV and IP therapy arm, suggesting that quantity of drug, known as dose density, may be the factor.
Biologic therapy is another area of interest that is being explored for ovarian cancer treatments. Researchers continue to study the benefits of targeted agents in the form ofmonoclonal antibodies and small molecules to treat a number of other cancers, including ovarian cancer. Anti-angiogenic agents, a form of targeted therapy that uses small molecule drugs or antibodies to stop tumors from making new blood vessels, have also shown promise in clinical settings. Trials are currently underway to investigate whether the addition of bevacizumab, a type of anti-angiogenic drug, to first-line treatment will improve clinical outcomes. In 2010, a study by the Gynecologic Oncology Group (GOG) found that women who received bevacizumab (Avastin) during their initial chemotherapy for ovarian cancer and continued up to 16 months after completion of initial chemotherapy had a reduced risk of progression of 28 percent compared to those who received chemotherapy alone. The benefit was short-lived leaving the community in a quandary regarding application of this therapy as a new standard of care. A newer study, reported this spring, the OCEANS trial, added bevacizumab to carboplatin and gemcitabine for women with first recurrence of ovarian cancer. There was a greater reduction in risk of progression in this study and an improvement in overall survival. How these studies will change practice patterns for the future is not yet known.
One of the most exciting recent advances in ovarian cancer has been the discovery and use of a new class of targeted agents, the PARP inhibitors. Olaparib, one type of PARP inhibitor, blocks the activity of PARP1 and PARP2 proteins that are necessary for cells to repair damaged DNA. This agent was found to be clinically active in breast and ovarian cancer patients who carry germ line mutations in the BRCA1 or 2 genes, and olaparib has also been active in high grade serous ovarian cancer, a type of epithelial ovarian cancer. Researchers hope that combining a PARP inhibitor, like olaparib, with traditional chemotherapy drugs, such as the platinums, will produce greater anticancer effects than either chemotherapy or a PARP inhibitor alone. This approach is based on the observation that cells are unable to survive if they accumulate high levels of DNA damage. Additional PARP-inhibitors are now under development and their roles are being investigated in women who are both BRCA1 and 2 mutation carriers and other women with ovarian cancer.
Acknowledging the poor prognosis of ovarian cancer, The Cancer Genome Atlas (TCGA) sponsored by the NCI, selected serous ovarian cancer, the most prevalent form of the disease, as one of the first to have its genomic changes charted in depth. The goal of the TCGA profiling was to look for gene expression patterns that are linked to differences in patient survival and to establish whether certain gene changes can be linked to response to therapy. To date, TCGA has achieved comprehensive sequencing, characterization, and analysis of the genomic changes in ovarian cancer. Their initial findings, just reported in the journal Nature, were of interest to many investigators. It showed that there are no frequent driving genetic mutations in ovarian cancer as has been shown in many other solid tumors. Serous ovarian cancer distinguished itself by its genetic complexity and variability. Investigators are now combing this remarkable data collection to identify leads for typing ovarian cancer in ways that will focus therapy for greater clinical benefit, survival advantages, and to reduce toxicity and patient injury.
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